hyper-IgE Research Articles

The Radiological Manifestations of Phagocytic Primary Immunodeficiencies in Children.

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient's clinical course, presentation features, and laboratory data. Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job's syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary noduleswithout halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians' awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

P20 Job syndrome: hyper IgE syndrome in a young girl with an acneiform rash

Abstract Hyper IgE syndrome (HIES1) is a rare, autosomal dominant, primary immunodeficiency characterized by eczema, recurrent staphylococcal skin infections, pneumonia, increased serum IgE and eosinophilia. It is caused by a heterozygous mutation in the STAT3 gene on chromosome 17q21 with variable expressivity. Nonimmunological findings including characteristic facies, hyperextensibility, long-bone fractures, aneurysms, craniosynostosis and dental abnormalities. We present the case of an 11-year-old girl referred to dermatology with an acneiform facial rash. Examination was consistent with papulo-pustular scarring acne of the face and back. Her history was also significant for recurrent MSSA bacterial lymphadenitis requiring incision and drainage over the proceeding 3 years. Her past medical history was significant for the development of moderate-severity infantile acne at 2 weeks of age, mild childhood eczema, recurrent childhood otitis media Staphylococcus infections resulting in grommet insertion, primary tooth retention requiring extraction and a fractured wrist at age 9 years. Because of the burden of infection the patient was referred to immunology in Crumlin. Investigations revealed mild neutropenia, marginally elevated IgA and IgM, normal eosinophils, marginally elevated IgE, normal lymphocyte subsets, intact complement pathways and normal oxidative burst test. Next-generation sequencing was significant for STAT3 gene mutation consistent with HIES. As there is no family history this likely represents a de novo mutation. The patient is currently on prophylactic azithromycin and low-dose isotretinoin with good effect. This case represents a patient with both immunological and nonimmunological features of HIES1, marginally elevated IgE, absence of eosinophils and negative family history.

Single-cell multi-omics sequencing reveals the immunological disturbance underlying STAT3-V637M Hyper-IgE syndrome

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by, among others, the excessive production of IgE and repetitive bacterial/fungal infections. Mutations in STAT3, a transcription factor that orchestrates immune responses, may cause HIES, but the underlying mechanisms are not fully understood. Here, we used multi-omic approaches to comprehensively decipher the immune disturbance in a male HIES patient harboring STAT3-V637M. In his peripheral blood mononuclear cell (PBMC) we found significant clonal expansion of CD8 T cells (with increased CD8 subunits expression, potentially enhancing responsiveness to MHC I molecules), but not in his CD4 T cells and B cells. Although his B cells exhibited a higher potential in producing immunoglobulin, elevated SPIC binding might bias the products toward IgE isotype. Immune checkpoint inhibitors, including CTLA4, LAG3, were overexpressed in his PBMC-CD4 T cells, accompanied by reduced CD28 and IL6ST (gp130) expression. In his CD4 T cells, integrative analyses predicted upstream transcription factors (including ETV6, KLF13, and RORA) for LAG3, IL6ST, and CD28, respectively. The down-regulation of phagocytosis and nitric oxide synthesis-related genes in his PBMC-monocytes seem to be the culprit of his disseminated bacterial/fungal infection. Counterintuitively, in his PBMC we predicted increased STAT3 binding in both naïve and mature CD4 compartments, although this was not observed in most of his PBMC. In his bronchoalveolar lavage fluid (BALF), we found two macrophage subtypes with anti-bacterial properties, which were identified by CXCL8/S100A8/S100A9, or SOD2, respectively. Together, we described how the immune cell landscape was disturbed in STAT3-V637M HIES, providing a resource for further studies.

Ovarian tissue cryopreservation in a girl with hyper-IgE syndrome (HIES) -A Case Report

Background: Ultra-high-dose radiotherapy and chemotherapy before hematopoietic stem cell transplantation (HSCT) will seriously damage ovarian function, resulting in premature ovarian insufficiency and poor quality of life. The most common indication of HSCT is hematonosis such as leukemia. However, it is often ignored that HSCT is also an effective therapy for some rare diseases such as some immune deficiency diseases. Therefore, medical practitioners should pay attention to the fertility preservation of patients with rare diseases who need HSCT. In this case, the girl with HIES needed HSCT because of the lung infection that could not be alleviated by antibiotics. Ovarian tissue cryopreservation was performed before HSCT which has successfully protected fertility.

Hyper IgE syndrome with congenital hypothyroidism: a rare association

Hyper IgE syndrome (HIES) is a rare immunodeficiency syndrome, with autosomal dominant inheritance, caused mainly due to STAT 3 mutation. The affected children usually present with atopic dermatitis, recurrent staphylococcal infections, phenotypic characteristics and increased IgE levels. Though, there is a case report of autoimmune thyroiditis in HIES, congenital hypothyroidism is not reported. Here we report a case of HIES with typical phenotypic features with congenital hypothyroidism that presented to us with recurrent infections, atopic dermatitis and pneumatocele of right lung. Child was subsequently managed with antibiotics, levothyroxine and lobectomy.

Kawasaki Disease and Inborn Errors of Immunity: Exploring the Link and Implications

The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott–Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature.

New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.

Inherited human ZNF341 deficiency.

Typical hyper-IgE syndromes (HIES) are caused by autosomal-dominant-negative (DN) variants of STAT3 (Signal Transducer And Activator Of Transcription 3) or IL6ST (Interleukin 6 Cytokine Family Signal Transducer), biallelic partial loss-of-function (LOF) variants of IL6ST, or biallelic complete LOF variants of ZNF341 (Zinc Finger Protein 341). Including the two new cases described in this review, only 20 patients with autosomal-recessive (AR) ZNF341 deficiency have ever been reported. Patients with AR ZNF341 deficiency have clinical and immunological phenotypes resembling those of patients with autosomal-dominant STAT3 deficiency, but with a usually milder clinical presentation and lower NK (Natural Killer) cell counts. ZNF341-deficient cells have 50% the normal level of STAT3 in the resting state. However, as there is no clear evidence that STAT3 haploinsufficiency causes HIES, this decrease alone is probably insufficient to explain the HIES phenotype observed in the ZNF341-deficient patients. The combination of decreased basal expression level and impaired autoinduction of STAT3 observed in ZNF341-deficient lymphocytes is considered a more likely pathophysiological mechanism. We review here what is currently known about the ZNF341 gene and ZNF341 deficiency, and briefly discuss possible roles for this protein in addition to its control of STAT3 activity.

DIVERSE NEUROLOGICAL MANIFESTATION OF HYPERIMMUNOGLOBULIN-E SYNDROME: A CASE SERIES

Hyper-immunoglobulin E (IgE) is a disorder of immune system characterized by assemblage of symptoms including recurrent skin and pulmonary infections, skeletal anomalies and elevated serum IgE (>2000 IU/ml). More recently, apart from the typical features, neurological manifestations have also been described including central nervous system infections, facial nerve palsy and demyelinating disorders. Here we describe three patients with hyper IgE syndrome having diverse neurological manifestation varying from CNS infection to basal ganglia stroke and progressive leukoencephalopathy.

Quality of Life Evaluation in Saudi Arabian Pediatric Patients with Primary Immunodeficiency Diseases Receiving 20% Subcutaneous IgG Infusions at Home.

Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG. In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG. Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients' diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients' global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients' general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively). This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.

Atypical Cutaneous Viral Infections Reveal an Inborn Error of Immunity in 8 Patients.

Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.

Successful treatment of DOCK8 deficiency by allogeneic hematopoietic cell transplantation from alternative donors.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by eczematous dermatitis, elevated serum IgE, and recurrent infections, comprising a seemingly hyper-IgE syndrome (HIES). DOCK8 deficiency is only curable with allogeneic hematopoietic cell transplantation (HCT), but the outcome of HCT from alternative donors is not fully understood. Here, we describe the cases of two Japanese patients with DOCK8 deficiency who were successfully treated by allogeneic HCT from alternative donors. Patient 1 underwent cord blood transplantation at the age of 16years, and Patient 2 underwent haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide at the age of 22years. Each patient received a fludarabine-based conditioning regimen. Their clinical manifestations, including refractory molluscum contagiosum, promptly improved post-HCT. They achieved successful engraftment and immune reconstitution without serious complications. Alternative donor sources such as cord blood and haploidentical donors can be options for allogeneic HCT for DOCK8 deficiency.

Challenges of Diagnostic Approach in a Hyper-IgE Syndrome Family

Introduction: Hyper IgE syndrome (HIES), formerly known as Job’s syndrome, is an inborn error of immunity (IEI) with variable clinical presentations of infection, allergies, and high IgE levels. HIES has recently become better defined by genetic defects in STAT3, DOCK8, IL6R, and IL6ST, among others. Identifying defects in these genes can serve as a diagnostic method alongside scoring reports such as the NIH HIES scoring system. However, some patients may present with clinical manifestations that are unaccompanied by an identified pathogenic variant. Here, we highlight challenges in the diagnostic approach of HIES in an affected family. MethodsA retrospective data collection of the clinical history, symptoms, demographics, and treatment outcomes of the proband and his affected father was performed. Extensive immune subset phenotyping and functional assays on the signaling pathways were also conducted. Genetic evaluation was also completed and included 207-gene panel testing and whole exome sequencing. ResultsThe 15-year-old proband’s clinical history included significantly elevated IgE levels, eczema, lymphadenopathy, and severe, treatmentresistant herpes infections that led to two hospitalizations within the last year. His NIH HIES score was determined to be 45. His father experienced frequent herpes infections and recurrent abscesses and is also in remission for non-Hodgkin’s lymphoma. A 207 Invitae testing panel showed that neither individual had a pathogenic variant observed in STAT3 or DOCK8. Flow cytometric analysis revealed reduced memory and expanded CD19hi CD21lo B-cell populations in both the proband and father. Th2 skewing was seen in the CD4+ memory T cells of both individuals, along with increased fractions of CD4+ recent thymic emigrants and exhausted T cells. Notably, functional assays also revealed elevated phosphorylation of ERK, JNK, and AKT, while the phosphorylation of STAT5 in the naive compartment was lowered. Although these findings are not normally observed in STAT3 loss of function, they may be indicative of IL-2 signaling defects. ConclusionsDespite both the proband and the father exhibiting many clinical manifestations of HIES and scoring highly in the NIH HIES scoring system, the underlying IEI remains unidentified. Functional studies and extensive genetic analysis are vital for making clinical decisions and determining targeted therapies.

Use of Dupilumab in HyperIgE syndrome with ERBIN-deficiency: case report

HyperIgE Syndromes (HIES) are rare primary immunodeficiencies characterized by recurrent infections and Th2 clinical signature (elevated IgE, eosinophilia, asthma, and atopic dermatitis). The major genetic alterations concern loss of function mutations of the STAT3/ERBIN/SMAD2/3 complex. Patients with ERBIN-deficiency have a higher number of Treg and greater IL-4Rα expression on naïve lymphocytes, due to increased activation of the TGF-ß pathway. Dupilumab is an anti-IL-4Rα monoclonal antibody that inhibits IL-4 and IL-13 signalling and the expression of type 2 cytokines. We here discuss a case of Dupilumab treatment in a ERBB2IP mutated patient. At our Rare Diseases referral Centre, we have been following a 20-year-old patient with severe atopic dermatitis, history of recurrent sinopulmonary infections, asthma and IgE level of 8818kU/L. On physical examination, the patient presented diffuse eczema with areas of lichenization, Eczema Area and Severity Index 29, Numeric Rating Scale of itch 9/10, Dermatology Life Quality Index 28/30, saddle nose, prognathism and severe left-convex scoliosis with NIH-HIES score equal to 37. CD4T lymphocytes were mainly Th2 (52%); Th17 were 13%, with normal IgG, IgA and IgM levels. The NGS genetic study found the following mutation of ERBB2IP, which encodes for ERBIN protein, likely pathogenic for HIES, together with a TMC8 and a CASP10 variant, all in heterozygosis. Given the underlying immunodeficiency and the non-response to topical and systemic corticosteroids, therapy with cyclosporine was not considered. Dupilumab was instead started with an induction dose of 600 mg and maintenance of 300 mg every 15 days. At last follow-up (14 months after dupilumab initiation) the patient presents: subjective well-being, skin free from manifestations, EASI score 0, NRS 0/10, DLQI 0/30, normal lung function with optimal control of asthma, IgE still>5000 kU/L. Of note, no more infectious episodes were reported. In our patient, given the anamnestic context of immunodeficiency, the use of target therapy on IL-4/IL-13R signalling proved to be particularly effective and safe in the treatment of skin manifestations related to the loss of function mutation of the ERBIN gene, known for the functional relationship with STAT3 in the regulation of IL-4Rα expression on naïve lymphocytes and of the Th2 response.

Dedicator of cytokinesis 8 (DOCK8) is a negative regulator of skin mast cell function

Abstract Dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. In humans, homozygous or compound heterozygous deletions of DOCK8 cause a combined immunodeficiency characterized by allergic disorders. Based on this evidence, we hypothesized that DOCK8 may be a negative regulator of mast cell function. To address this hypothesis, we used mice with a loss-of-function mutation in Dock8 (primuris, Dock8 pri/primice) and conditional mice in which DOCK8 is ablated in connective tissue mast cells (Mcpt5-Cre +; Dock8 fl/flmice). Dock8 pri/primice exhibited increased plasma levels of mast cell protease-1 (MCPT1) in homeostatic conditions. Furthermore, Dock8 pri/primice and Mcpt5-Cre +; Dock8 fl/flmice experienced a more severe IgE-dependent passive cutaneous anaphylactic reaction (PCA) than control mice. This data suggests that DOCK8 deficiency is linked to increased mast cell activation in homeostatic conditions and upon stimulation by IgE-dependent mechanisms. Fetal skin derived cultured mast cells (FSMCs) generated from Dock8 pri/primice released increased amounts of β-hexosaminidase upon IgE-dependent activation. Consistent with this finding, naïve DOCK8-deficient FSMCs exhibited alterations in cytoskeletal dynamics that may facilitate mast cell degranulation. Finally, we observed an increased number of tryptase positive cells in skin biopsies obtained from three pediatric patients diagnosed with hyper IgE syndrome (HIES) due to DOCK8 mutations, suggesting that DOCK8 immunodeficiency may contribute to skin mast cell expansion in humans. Our findings provide strong evidence that DOCK8 can contribute to negative regulation of skin mast cell activation and expansion. R01 AI140626-05

Molecular profile of patients with inborn errors of immunity from Nepal

Background and AimsInborn errors of immunity (IEIs) are increasingly being diagnosed in various regions of the world. There are significant challenges in the diagnosis and treatment of IEIs in resource-limited countries. With the availability of one immunologist and increasing awareness, IEIs are diagnosed with increasing frequency and accuracy in Nepal. IEIs are also being evaluated in children presenting with autoimmune manifestations. We describe the profile of patients diagnosed with IEIs in Nepal during 2020–2022. MethodsRecords of all patients with IEIs who were diagnosed and treated at our tertiary care center in Nepal from August 2020 to April 2022 were analysed. Lead author (DB) has examined and diagnosed all cases. IEIs were diagnosed based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and genetic analysis. ResultsThirty-two patients with IEI (19 boys; 13 girls) and 801 children with autoimmune disorders were diagnosed during the study period. Genetic analysis was done on 18 patients. The diagnostic profile of the patients includes patients with chronic granulomatous disease, X-linked agammaglobulinemia, severe combined immunodeficiency, Job syndrome, selective IgA deficiency, specific antibody deficiency, Wiskott-Aldrich Syndrome, CTLA4 deficiency, IPEX syndrome, IFN-IL12 axis defect, hereditary angioedema, MonoMac syndrome, ARPC1B deficiency, leukocyte adhesion defect, PAPA syndrome, autoimmune lymphoproliferative syndrome, ADA2 deficiency, early-complement deficiency lupus, familial cold auto-inflammatory syndrome, A20 haploinsufficiency, and Blau syndrome. Some patients succumbed before the scope of diagnosis. HSCT is planned for 3 patients. ConclusionsOur is the first report of genetically proven IEIs in Nepal. Logistic constraints coupled with a lack of awareness of IEIs among laity and pediatrician accounted for a missed diagnosis, late diagnosis, and poor outcomes in resource-limited settings. Antimicrobial prophylaxis reduced the incidence of breakthrough infections. The lack of HSCT facilities precludes definitive treatment of many IEIs.

Renal Disease in Inborn Errors of Immunity: a Case Series

Renal disease is an underappreciated complication of inborn errors of immunity (IEIs). Chronic kidney disease (CKD) is associated with significant morbidity and mortality in the general population; however, clinical experience with CKD in IEIs is limited. We examined the age of onset, progression, and outcomes of CKD in 4 adult IEI patients seen at our centre. Immunologic diagnoses for all patients were made clinically and with the support of genetic testing. Renal biopsy pathology reports, age at symptom onset and diagnosis of IEI, age at diagnosis of CKD, serum creatinine levels, and measures of proteinuria were assessed.We reviewed the charts of four patients with IEIs and CKD. The IEI diagnoses were: 1) STAT3 loss-of-function (Job syndrome), 2) common variable immunodeficiency (CVID) with compound heterozygous TNFRSF13B (TACI) variants, 3) CVID with negative whole exome sequencing (WES), and 4) combined immunodeficiency with negative WES. All patients received renal biopsy-confirmed diagnoses of CKD. Biopsies were performed between adolescence and adulthood (mean age 27.25 years, range 18–35), on average 18.5 years after their initial symptoms of an underlying IEI (range 13–24 years). The histopathological diagnoses respectively were 1) immune complex-mediated mesangial proliferative and membranous glomerulonephritis, 2) interstitial nephritis with glomerulosclerosis and interstitial fibrosis with lymphocytic infiltration likely from lymphoma, 3) granulomatous infiltration from underlying CVID, and 4) lupus nephritis predominantly with proteinuria. In all cases, despite treatment, renal disease was non-reversible. One patient required renal transplantation, and one patient became dialysis dependent. For two patients, renal function stabilized but did not revert to pre-disease levels. Renal disease is a potentially serious comorbidity that can develop in IEIs, predisposing to further infections and impairing quality of life. Practitioners caring for people with IEIs should be aware that CKD can affect young adults and may present several years from IEI symptom onset. Monitoring for renal disease and prompt referral to a nephrologist for potential treatment should be pursued, as recognizing CKD in its early stages may help prevent or slow progression.

DOCK 8 IMMUNODEFICIENCY

Autosomal recessive (AR) DOCK8 deciency is a well-known actinopathy, a combined primary immune deciency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-decient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic aetiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favour of genetic defects. We describe a school-age female patient with a clinical picture suggestive of DOCK8 deciency, except for high serum IgE or a family history: early onset, failure to thrive, oral fungating lesion, generalized maculopapular rashes, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leucocytosis, eosinophilia, high IgA, low IgG and low CD4+ T cells. We were able to conrm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-decient patients. Despite this, the constellation of signs, symptoms, and ndings allow the suspicion of DOCK8 deciency and other actinopathies.

High rate of molecular diagnosis among individuals with alopecia with known or suspected inborn errors of immunity

Background and aimsAlopecia is a multifactorial disorder causing hair loss of the scalp, face, and/or body. It affects an estimated 0.1–0.2% of individuals worldwide and can be visually stigmatizing and have significant quality of life consequences. While most cases of alopecia lack an identifiable genetic explanation, this condition is enriched in individuals with Mendelian inborn errors of immunity (IEI). The purpose of this study was to determine Mendelian contributions to alopecia in a mixed cohort of patients with suspected IEI. MethodsThe cohort was comprised of 3,072 unrelated participants with suspected IEI or related inflammatory disorders who underwent exome and/or genome sequencing from 2017–2022. From this pool, we identified 110 (3.58%) probands with alopecia. ResultsProbands were predominantly adult (mean 37.2 years, range 4–76), female (67%), and of European ancestry (64.5%). Alopecia was characterized as universalis (3/110, 2.7%), totalis (4/110, 3.6%), areata (5/110, 4.5%), scarring alopecia of the scalp (2/110, 1.8%), and other or not otherwise specified (96/100, 87.3%). Overall, 33/110 probands (30.0%) were found to have a Mendelian molecular diagnosis. Almost half of the participants with molecular diagnoses (15/33, 45%) had biallelic defects in AIRE, consistent with a molecular diagnosis of autoimmune polyendo-crinopathy-candidiasis-ectodermal dystrophy (APECED). In addition, 4/33 (12.1%) had a molecular diagnosis of STAT3-related hyper-IgE syndrome, 2/33 (6.1%) had STAT1 deficiency, and 2/33 (6.1%) had RAG1 deficiency. The remaining 10/33 (30.3%) included defects in the following genes: CXCR4, FAM111B, FOXN1, GATA2, IL2RG, GJB2, NFKB2, PIK3CD, PLCG2, and PSMB8. Multiple linear regression found that when controlling for sex and ancestry, younger age and greater phenotypic complexity was significantly associated with the likelihood of receiving a molecular diagnosis related to alopecia (OR = 0.93, p-value = 0.004 and OR = 1.27, p-value = 0.034, respectively). ConclusionsIn summary, a high proportion of individuals with alopecia in an IEI cohort received a molecular diagnosis via WES/WGS. Further, there was a small but significant association between younger age and higher phenotypic complexity and likelihood of receiving a molecular diagnosis. Most molecular diagnoses for alopecia in this cohort were disorders of the immune system, while two (hereditary fibrosing poikiloderma and keratitis-ichthyosis deafness syndrome) involved primarily non-immune etiologies.

Loss of Stat3 in Osterix+ cells impairs dental hard tissues development

BackgroundMutations in the signal transducers and activators of transcription 3 (STAT3) gene result in hyper-IgE syndrome(HIES), a rare immunodeficiency that causes abnormalities in immune system, bones and teeth. However, the role of Stat3 in development of dental hard tissues was yet to investigate.MethodsIn this study, a transgenic mouse of conditional knockout of Stat3 in dental mesenchymal cells (Osx-Cre; Stat3fl/fl, Stat3 CKO) was made. The differences of postnatal tooth development between control and Stat3 CKO mice were compared by histology, µCT and scanning electron microscopy.ResultCompared with the control, Stat3 CKO mice were presented with remarkable abnormal tooth phenotypes characterized by short root and thin dentin in molars and incisors. The enamel defects were also found on mandibular incisors. showed that Ki67-positive cells significantly decreased in dental mesenchymal of Stat3 CKO mice. In addition, β-catenin signaling was reduced in Hertwig's epithelial root sheath (HERS) and odontoblasts of Stat3 CKO mice.ConclusionsOur results suggested that Stat3 played an important role in dental hard tissues development, and Stat3 may regulate dentin and tooth root development through the β-catenin signaling pathway.